Intracellular receptors (IR) form a class of structurally related gene regulators known as “ligand dependent transcription factors” (Mangelsdorf, D. J. etc. Cell, 83, 835, 1995). The steroid receptor family is a subset of the IR family, including progesterone receptor (PR), estrogen receptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).
The natural hormone, or ligand, for the PR is the steroid progesterone. Synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, can
The natural hormone, or ligand, for the PR is the steroid progesterone. Synthetic compounds, such as medroxyprogesterone acetate or levonorgestrel, can also serve as PR ligands. Once a ligand is present in the fluid surrounding a cell, it passes through the membrane via passive diffusion, and binds to the IR to create a receptor/ligand complex. This complex binds to specific gene promoters present in the cell's DNA. Once bound to the DNA the complex modulates the production of mRNA and the protein encoded by that gene.
A compound that binds to an IR and mimics the action of the natural hormone is termed an agonist, whilst a compound which inhibits the effect of the hormone is an antagonist.
PR agonists (natural and synthetic) are known to play an important role in the health of women. PR agonists are used in birth control formulations, either along or in the presence of an ER agonist. ER agonists are used to treat the symptoms of menopause, but have been associated with a proliferative effect on the uterus which can lead to an increased risk of uterine cancers. Co-administration of a PR agonist reduces/ablates that risk.
PR antagonists may also be used in contraception. In this context they may be administered alone (Ulmann, et al., Ann. N.Y. Acad. Sci., 261, 248, 1995), in combination with a PR agonist (Kekkonen, et al, Fertility and Sterility, 60, 610, 1993) or in combination with a partial ER antagonist such as tamoxifen (U.S. Pat. No. 5,719,136).
PR antagonists may also be useful for the treatment of hormone dependent breast cancers (Horwitz, et al, Horn. Cancer, 283, 1996, pub: Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovarian cancers. PR antagonists may also be useful for the treatment of non-malignant chronic conditions such as uterine fibroids (Murphy, et al, J. Clin. Endo. Metab., 76, 513, 1993) and endometriosis (Kettel, et al., Fertility and Sterility, 56, 402, 1991).
PR antagonists may also be useful in hormone replacement therapy for post menopausal patients in combination with a partial ER antagonist such as tamoxifen (U.S. Pat. No. 5,719,136).
PR antagonists, such as mifepristone and onapristone, have been shown to be effective in a model of hormone dependent prostate cancer, which may indicate their utility in the treatment of this condition in men (Michna, et al, Ann. N.Y. Acad. Sci., 761, 224, 1995).
PR ligands have been described, for example, in Zhi, et al, (Bioorg. & Med. Chem. Lett. 10, 415, 2000 and J. Med. Chem., 41, 291, 1998), Tegley, et al (J. Med. Chem. 41, 4357, 1998), Combs, et al. (J. Med. Chem., 38, 4880, 1995), Perlman, et. al. (Tet. Letters, 35, 2295, 1994), Hamann, et al (Ann. N.Y. Acad. Sci., 761, 383, 1995), Chen, et al (Chen, et al, POI-37, 16th Int. Cong. Het. Chem., Montana, 1997), Kurihari, et. al., described the PR ligand 12 (J. Antibiotics, 50, 360, 1997).
Zhang, et al., described several PR modulators (U.S. Pat. Nos. 6,432,949, 6,380,235, and 6,358,948). Other PR modulators are described in Fensome, et al. (U.S. Pat. Nos. 6,391,907 and 6,355,648), Santilli, et al (U.S. Pat. No. 6,306,851), Zhang, et al. (U.S. Pat. No. 6,369,056), Ullrich, et al. (U.S. Pat. No. 6,417,214), and Collins, et al. (U.S. Pat. Nos. 6,407,101 and 6,339,098).
Certain 4,1-benzoxazepinones are disclosed in the art. PCT Patent Application WO 99/11635 describes the use of some 5,5-disubstituted-1,5-dihydro-4,1-benzoxazepinones as HIV reverse transcriptase inhibitors. PCT Patent Application WO 97/48701 discloses certain squalene synthetase inhibitor 4,1-benzoxazepinones with a linked carboxyl group at position 3. Japanese Patent Application JP 08-259447 and European Patent Application EP 0567026 disclose certain 4,1-benzoxazepinones. U.S. Pat. No. 4,476,133 describe the use of some 5-substituted-4,1-benzoxazepinones as CNS agents. European Patent Application EP 0142361 discloses phospholipase A2 inhibitor benzoxazepinones.